Bcl-2 inhibition sensitizes triple-negative human breast cancer cells to doxorubicin
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Touko Inao1,2, Yuichi Iida1, Tamami Moritani1, Tamio Okimoto3, Ryosuke Tanino3, Hitoshi Kotani1 and Mamoru Harada1
1Department of Immunology, Shimane University Faculty of Medicine, Shimane, Japan
2Department of Breast Surgery, Takasago City Hospital, Hyogo, Japan
3Division of Medical Oncology & Respiratory Medicine, Department of Internal Medicine, Shimane University Faculty of Medicine, Shimane, Japan
Mamoru Harada, email: [email protected]
Keywords: breast cancer; triple-negative; Bcl-2; ABT-199; doxorubicin
Received: March 20, 2018 Accepted: April 24, 2018 Published: May 22, 2018
Breast cancers can be divided into several types. Because triple-negative breast cancer (TNBC) is the most refractory to current anti-cancer therapies, efficient treatment has been urgently required. Members of the Bcl-2 family play pro- and anti-apoptotic roles in mitochondria-mediated apoptosis. Some Bcl-2 family members are expressed in breast cancer and influence the response to anti-cancer therapies. In this study, we investigated whether Bcl-2 inhibition could sensitize TNBC cells to the genotoxic drug doxorubicin (DR). Treatment with a combination of the Bcl-2 inhibitor ABT-199 and DR synergistically decreased the viability of the TNBC cell lines MDA-MB-231 and BT-549. In an apoptosis assay, the combination treatment resulted in only a marginal effect in BT-549 cells, whereas drastic apoptosis was induced in MDA-MB-231 cells treated with both ABT-199 and DR. Both caspase-8 and -9 were involved in the combination treatment-induced apoptosis. Short interfering RNA-mediated knockdown of Bcl-2 increased the sensitivity of both cell lines to DR. The combination treatment also significantly decreased the colony-forming ability of the TNBC cell lines. In a xenograft mouse model, oral administration of ABT-199 augmented the DR-induced antitumor effect on subcutaneously established MDA-MB-231 cells. These results indicate that the combination of DR with Bcl-2 inhibitors, including ABT-199, may be a promising treatment modality for TNBC patients.
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